BACKGROUND: Little is known about the causes of serum aquaporin 4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (AQP4-positive NMOSD) or how its pathophysiology differs from other demyelinating autoimmune diseases, which limits therapeutic and preventative opportunities despite available diagnostic biomarkers. By performing a pan-ancestry genome-wide association study (GWAS), we aimed to deepen our understanding of the genetic architecture of AQP4-positive NMOSD and to explore shared heritability with other autoimmune diseases. METHODS: We performed a pan-ancestry GWAS in 2833 individuals, including 1573 AQP4-positive NMOSD cases and 1260 controls (comprising non-affected relatives, healthy non-relatives, and those with other autoimmune diseases). Samples were collected from the International NMOSD Genetics Consortium, comprising 36 hospitals and research facilities across the world. All individuals with AQP4-positive NMOSD fulfilled the 2015 international consensus diagnostic criteria for NMOSD, including positive AQP4-IgG status. We also performed a second GWAS with only the 1857 samples of European ancestry (803 cases and 1054 controls). We then compared our GWAS findings to those from other autoimmune diseases. FINDINGS: We found three independent associations with AQP4-positive NMOSD that reached genome-wide significance: two within the MHC and a third within an intron of the STAT4 gene. In the pan-ancestry study, we identified a complement C4A-associatied variant, rs1150753 (chr6:32092090:A>G, p=1·61 × 10-29, odds ratio [OR] 2·95, 95% CI 2·44-3·56), rs607929 (chr6:32619221:C>G, p=2·87 × 10-24, OR 1·93, 95% CI 1·70-2·20), and a STAT4-associated variant, rs35593987 (chr2:191051800:AC>A, p=8·49 × 10-14, OR 1·75, 95% CI 1·51-2·03). In Europeans, we identified variants that were either in linkage disequilibrium with or the same as those from the pan-ancestry study: rs1270942 (chr6:31951083:A>G, p=2·52 × 10-28, OR 3·01, 95% CI 2·47-3·66), rs607929 (p=1·12 × 10-20, OR 1·99, 95% CI 1·72-2·30), and rs3821236 (chr2:191038032:G>A, p=1·20 × 10-10, OR 1·74, 95% CI 1·47-2·06). rs1270942 is in linkage disequilibrium with rs1150753 (r2=0·96) as well as two AQP4-positive NMOSD-associated HLA alleles, HLA-DRB1*03:01 (p=2·80 × 10-26, OR 2·79, 95% CI 2·30-3·37) and HLA-B*08:01 (p=1·02 × 10-24, OR 2·68, 95% CI 2·22-3·24). A priori testing of the P1104A variant (rs34536443, chr19:10352442:G>C) within the TYK2 gene, which acts upstream in the STAT4 pathway, found it to be protective (p=0·0008, OR 0·52, 95% CI 0·35-0·76 in the pan-ancestry study). Genetic sharing was observed with several comorbid autoimmune diseases for both the complement C4A-associated and STAT4-associated variants, including Sjögren's syndrome and systemic lupus erythematosus. INTERPRETATION: AQP4-positive NMOSD is more genetically similar to systemic autoimmune diseases than to multiple sclerosis, despite sharing overlapping clinical phenotypes. Specifically, a polymorphism associated with reduced complement C4 was identified as the biggest disease genetic risk factor, which has been shown to facilitate the development of autoantibody-producing B cells. Our findings also support a pathogenic role of HLA-restricted CD4+ T cells, owing to both a genome-wide significant association of HLA-DRB1*03:01 as well as heritable risk within the TYK2-STAT4 signalling pathway. Having already been shown to be a successful target for treating psoriatic arthritis and, potentially, systemic lupus erythematosus, we propose the TYK2-STAT4 pathway as a possible therapeutic target in AQP4-positive NMOSD. FUNDING: The OAK Foundation, The Guthy Jackson Charitable Trust Foundation, and the UK Medical Research Council.